Thiazole Derivatives for Treating Restless Legs Syndrome

ABSTRACT

The invention relates to the use of derivatives of thiazoles having general formula (I) for the preparation of a medicament for the treatment or prevention of restless legs syndrome, also known as Ekbom syndrome. The invention also relates to a combination of thiazole derivatives having general formula (I) and at least one compound selected from among neuroleptics or products that act on the dopaminergic system for the treatment or prevention of restless legs syndrome, also known as Ekbom syndrome.

A subject of the present invention is thiazole derivatives of general formula (I) described below for preparing a medicament intended for treating or preventing restless legs syndrome, also called Ekbom syndrome.

Restless legs syndrome is a neurological disorder characterized by a sensation of agitation in the lower limbs as well as by paresthesias. This disorder is accompanied by disagreeable sensory disorders and/or involuntary movements in the legs, more rarely in the arms. Akathisia which is an inability to sit still, or tasikinesia which is an inability to stay in the same place are also noted. Among the symptoms, paresthesias (tingling, pins and needles), more or less sudden twitches, irritations in the legs and sometimes pain are also noted.

Typically, the disorders manifest themselves in the evening or at night, and occur when the patient is sitting quietly or lying in bed and diminish as soon as he takes a few steps or carries out an activity.

These convulsive movements can persist during sleep without the patient being aware of them. The term periodic limb movements in sleep (PLMS) is then used.

Sensory disorders and the irresistible need to move have as a consequence either difficulties with falling asleep and remaining asleep, or daytime sleepiness. Often, depression is also present.

The suspected causes of the disease would involve a lack of dopamine in the central nervous system. A genetic predisposition (idiopathic form) has been demonstrated. But other causes have also been mentioned: iron deficiency, chronic disease (diabetes, renal insufficiency, fibromyalgia, rheumatoid polyarthritis), pregnancy, Vitamin B complex deficiency. The syndrome could also be promoted by a treatment with medicaments (anti-depressants, neuroleptics, bronchodilators and calcium inhibitors).

Ekbom syndrome is a frequent ailment. It is estimated that the disease affects 5-10% of the population, women more than men.

Therapeutic treatments known at present are not satisfactory. In fact the recommended treatments include the dopaminergics (pramipexole, pergolide, ropinirole, levodopa/carbidopa) sedatives (benzodiazepines), narcotic analgesics (codeine, oxycodone) which are not without side effects, as well as motor activity such as walking or stretching, and also hot baths.

In order to meet patients' needs, it has become necessary to find a new means for treating this syndrome.

Thus the problem that the invention proposes to solve is to provide a novel compound suitable for treating Ekbom syndrome.

Unexpectedly, the Applicant has demonstrated that it is possible to use thiazole derivatives of general formula (I) described below for preparing a medicament intended for treating or preventing restless legs syndrome, also called Ekbom syndrome.

Finally the use according to the invention has the advantage of being able to be implemented in patients and animals suffering from these disorders.

Other advantages and characteristics of the invention will become clearly apparent on reading the following description and examples which are given purely by way of illustration and are in no way limitative.

The subject of the invention is the use of a compound of general formula (I)

in the form of racemic, enantiomeric mixture, or any combination of these forms, in which:

A represents a radical (A1)

in which R⁶ represents a hydrogen atom or an alkyl radical, R⁶, R⁷, R⁸ represent independently a hydrogen atom or an alkyl, cycloalkyl, hydroxy or alkoxy radical;

B represents a hydrogen atom or an alkyl radical;

n represents an integer from 0 to 5;

R¹ and R² represent independently a hydrogen atom or an alkyl or cycloalkyl radical;

R³ and R⁴ represent independently a hydrogen atom or an alkyl radical, or R³ and R⁴ form together with the nitrogen atom which carries them a heterocycle containing in all 1 to 2 heteroatoms and 5 to 7 members, a heterocycle the missing members of which are chosen from —CH₂—, —NR¹⁴—, —O— or —S—, R¹⁴ representing a hydrogen atom or an alkyl radical, or a —COR¹⁵, —COOR¹⁵ or —CONR¹⁶R¹⁷ radical, R¹⁵ representing an alkyl radical and R¹⁶ and R¹⁷ represent independently a hydrogen atom or an alkyl radical;

or of a salt of general formula (I) defined above for preparing a medicament intended for treating or preventing restless legs syndrome, also called Ekbom syndrome.

Within the meaning of the present invention, by alkyl or alkoxy radical, unless otherwise specified, is meant a linear or branched alkyl or alkoxy radical containing 1 to 6 carbon atoms. By radical cycloalkyl, unless otherwise specified, is meant a cycloalkyl radical containing 3 to 7 carbon atoms.

Preferably, by linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.

By pharmaceutically acceptable salt, is meant in particular within the meaning of the invention, addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate. Also included within the scope of the present invention, when they can be used, are the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference can be made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.

Moreover, certain compounds of general formula (I) can be presented in the form of enantiomers. The present invention includes the two enantiomeric forms and all combinations of these forms, including the “R, S” racemic mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.

Preferably, the compounds according to the invention are such that the R⁵ radical of A1 is a hydrogen atom.

Preferably, the compounds according to the invention are such that the R⁶, R⁷, R⁸ radicals of A1 represent independently a hydrogen atom or an alkyl radical.

Preferably, the compounds according to the invention are such that n is comprised between 0 and 3, more preferentially in that n is equal to 0.

More preferentially, the compounds according to the invention are such that R′ represents a hydrogen atom.

Still more preferentially, the compounds according to the invention are such that R² represents a hydrogen atom or an alkyl radical.

More particularly, the compounds according to the invention are such that R³ or R⁴ represents a hydrogen atom or an alkyl radical.

Still more particularly, the compounds according to the invention are such that they are the following compounds:

-   -   4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol;     -   4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;     -   4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

The synthesis of these compounds is described in the Application WO 01/26656.

Preferably, the purpose of the invention is the use of a compound of general formula (I) or a salt of general formula (I) defined above for preparing a medicament intended for treating or preventing restless legs syndrome, also called Ekbom syndrome.

The compound of general formula (I) or its salt used according to the invention or the combination according to the invention can be in solid form, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The compound of general formula (I) or its salt used according to the invention or the combination according to the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, similarly their mixtures, in varying proportions, in water.

The administration of a compound of general formula (I) or its salt used according to the invention or the combination according to the invention can be carried out for example by topical, oral, parenteral route, by intramuscular or sub-cutaneous injection. The envisaged administration dose can be comprised between 0.01 mg and 10 g depending on the type of active ingredient used. 

1. A method for treating or preventing restless legs syndrome, also called Ekbom syndrome, comprising administering a compound of general formula (I)

in which: A represents (A1)

in which R⁵ represents hydrogen or alkyl, R⁶, R⁷, and R⁸ represent independently hydrogen, alkyl, cycloalkyl, hydroxy, or alkoxy; B represents hydrogen or alkyl; n represents an integer from 0 to 5; R¹ and R² represent independently hydrogen, alkyl, or cycloalkyl; R³ and R⁴ represent independently hydrogen or alkyl, or R³ and R⁴ form together with the nitrogen atom to which they are attached a heterocycle comprising 1 to 2 heteroatoms and 5 to 7 members, wherein the members of the heterocycle include —CH₂—, —NR¹⁴—, —O— or —S—, R¹⁴ representing hydrogen, alkyl, —COR¹⁵, —COOR¹⁵, or —CONR¹⁶R¹⁷, R¹⁵ representing alkyl and R¹⁶ and R¹⁷ represent independently hydrogen or alkyl; or a salt of general formula (I) defined above.
 2. The method of claim 1, wherein R⁵ is hydrogen.
 3. The method of claim 1, wherein R⁶, R⁷, and R⁸ represent independently hydrogen or alkyl.
 4. The method of claim 1, wherein n is between 0 and
 3. 5. The method of claim 1, wherein n is equal to
 0. 6. The method of claim 1, wherein R¹ represents hydrogen.
 7. The method of claim 1, wherein R² represents hydrogen or alkyl.
 8. The method of claim 1, wherein R³ or R⁴ represents hydrogen or alkyl.
 9. The method of claim 1, wherein the compound is: 4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol; 4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol; or 4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol. 